In recent years carbon monoxide has been acknowledged as a fundamental small molecule messenger in mammals. The endogenous production of CO is associated with the heme metabolic pathway, in particular the action of a family of enzymes known as heme oxigenases, which catalyze the oxidation of heme to biliverdin and thereby liberate free iron and carbon monoxide. The tissue-specific distribution of heme oxigenases and, thus, the liberated carbon monoxide have been linked to several physiological effects. For example, carbon monoxide is a signaling molecule in the inducible defensive system against stressful stimuli; it has a fundamental role in the circulatory system by improving vasorelaxation and cardiac blood supply; it suppresses arteriosclerotic lesions associated with chronic graft rejection; like NO it influences neurotransmission in the hypothalamic-pituitary-adrenal axis and there is evidence that carbon monoxide influences the circadian rhythm of mammals by interacting with NPAS2, the so-called human “clock” protein.
Due to the relevance of carbon monoxide for mammalian physiology, the interest in its medicinal use is growing. Direct carbon monoxide inhalation was tested, but low tolerance to the compound proved contradictory because there is a delicate balance between carbon monoxide-induced tissue hypoxia and therapeutic benefits. Furthermore, the direct gaseous use leads to problems with safety as well as with targeted and controlled delivery. CO-releasing molecules (CO-RMs) represent an alternative approach to the administration of carbon monoxide. A number of complexes have been evaluated and pioneering work of Motterlini and Mann (e.g. Motterlini et al., Circ. Res., 2002 90, E17-24; Motterlini et al., Intensive Care Med. 2008, 34, 649-658; Motterlini et al., Circ. Res. 2002, 90, E17-24; Motterlini et al., Expert. Opin. Investig. Drugs 2005, 14, 1305-1318; Motterlini et al., Curr. Pharm. Des. 2003, 9, 2525-2539; Motterlini et al., J., FASEB J. 2005, 19, 284-286) resulted in the most promising fac-[RuCl(glycinato)(CO)3] complex (CO-RM-3) for controlled carbon monoxide release in vivo. The chemistry and therapeutic effects of CORM-3 are well-documented. CORM-3 releases one mol carbon monoxide within ten minutes after being dissolved in water and significantly reduces blood pressure in vivo and relaxes pre-contracted aortic rings in vitro. Its cardioprotective effects have been documented. Today metal carbonyls have been recognized as a potential new class of pharmaceuticals (for a review on CO-RMs see Johnson et al., Metal Carbonyls in Medicine, Angew. Chem. Int. Ed., 2003, 42, 3722-3729). There are a wide range of documented physiological and medically beneficial effects of CO. It is anti-inflammatory, e.g. it attenuates endotoxic shock and reduces allergic inflammation; it suppresses graft rejection; it protects against hyperoxia and oxidative lung injury; it protects against ischemia and reperfusion injury; it protects pancreatic beta cells from apoptosis; it modulates spermatogenesis under stress conditions; it decreases perfusion pressure; it protects against septic shock and lung injury; it provides cytoprotective effects; it modulates vascular smooth muscle tone, regulates blood pressure under stress conditions and suppresses arteriosclerotic lesions associated with chronic graft rejection and with balloon injury. For CO-RMs aortic vasodilatation, attenuated coronary vasoconstriction and reduction of hypertension was shown. For CO-RM3 inhibition of reperfusion injury, graft rejection and blood platelet aggregation was confirmed.
WO 02/092075 A2 pharmaceutical compositions comprising metal carbonyl compounds teaches, wherein the metal is selected from Fe, Mn, Ru, Rh, Ni, Mo or Co, for stimulating guanylate cyclase activity, neurotransmission or vasodilatation, for treating hypertension, radiation damage, endotoxic shock, inflammation, inflammation-related diseases, hyperoxia-induced injury, apoptosis, cancer, transplant rejection, arteriosclerosis, post-ischemic organ damage, myocardial infarction, angina, haemorrhagic shock, sepsis, penile erectile dysfunction and adult respiratory distress symptom.
Rhenium is an extremely rare group 7 transition metal that is mainly used for super-alloy and catalyst production. Radioactive isotopes 188Re and 186Re are presently used for treatment of liver cancer. They both have similar penetration depths in tissue (5 mm for 186Re and 11 mm for 188Re), but 186Re has the advantage of longer lifetime (90 hours vs. 17 hours for the 188 isotope). Related by periodic trends rhenium has a chemistry similar to technetium. Results on work done to label rhenium onto target compounds can often be transferred to technetium. This transfer aspect has proven useful for radiopharmacy, where it is difficult to work with technetium, especially with the medically used 99m isotope. So far medical applications of rhenium have been limited to the cytotoxic use of its radioactive isotopes.
Very recently Zobi et al. (Inorg. Chem. 2009, 48, 8965-8970) reported the synthesis of carbon monoxide-containing rhenium I and II complexes by means of a versatile synthetic intermediate [ReIIBr4(CO)2]2−, that is stable but sufficiently sensitive to substitution reactions with selected ligands. Due to the unexpected aerobic stability and well-behaved chemistry of complexes derived from this intermediate, the authors very generally speculated on possible medical applications of these ReI/II complexes in medicinal chemistry in the context of conventional Re use, i.e. as cytotoxic isotopes.
It is the object underlying the present invention to provide new medically useful rhenium compounds, preferably medically useful and non-radioactive rhenium compounds. Furthermore, it is an object to provide new carbon monoxide-releasing compounds for medical and/or diagnostic applications, in particular for the prophylaxis and/or treatment of diseases and/or medical conditions selected from the group consisting of cardiovascular diseases, preferably cardiac hypoxia, cardiac infarction, cardiac hypertrophy, arteriosclerosis and hypertension; ischemia-reperfusion injury, inflammatory diseases, preferably asthma or angina; traumatic injury, preferably of the brain, kidney or liver; transplant rejection, preferably allograft and xenograft rejection, platelet aggregation and/or monocyte activation; neuron degeneration of the nervous system, radiation damage, cancer, penile erectile dysfunction, adult respiratory distress syndrome, and disorders of the circadian rhythm of mammals, preferably jet lag.
A further object is to provide (i) new diagnostic and/or medical uses for rhenium compounds, in particular non-radioactive rhenium compounds as well as (ii) pharmaceutical and diagnostic compositions comprising said compounds.